Abstract
Tuning metal–support interaction has been considered as an effective approach to modulate the electronic structure and catalytic activity of supported metal catalysts. At the atomic level, ...the understanding of the structure–activity relationship still remains obscure in heterogeneous catalysis, such as the conversion of water (alkaline) or hydronium ions (acid) to hydrogen (hydrogen evolution reaction, HER). Here, we reveal that the fine control over the oxidation states of single-atom Pt catalysts through electronic metal–support interaction significantly modulates the catalytic activities in either acidic or alkaline HER. Combined with detailed spectroscopic and electrochemical characterizations, the structure–activity relationship is established by correlating the acidic/alkaline HER activity with the average oxidation state of single-atom Pt and the Pt–H/Pt–OH interaction. This study sheds light on the atomic-level mechanistic understanding of acidic and alkaline HER, and further provides guidelines for the rational design of high-performance single-atom catalysts.
N
6
-Methyladenosine (m
6
A) is the most common posttranscriptional modification of RNA and plays critical roles in cancer pathogenesis. However, the biological function of long noncoding RNA ...(lncRNA) methylation remains unclear. As a demethylase, ALKBH5 (alkylation repair homolog protein 5) is involved in mediating methylation reversal. The purpose of this study was to investigate lncRNA m
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A modification and its role in gastric cancer (GC). Bioinformatics predicted interactions of ALKBH5 with lncRNAs. Five methods were employed to assess the function of nuclear paraspeckle assembly transcript 1 (NEAT1), including gene silencing, RT-PCR, separation of nuclear and cytoplasmic fractions, scrape motility assays, and transwell migration assays. Then, m
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A RNA immunoprecipitation and immunofluorescence were used to detect methylated NEAT1 in GC cells. Rescue assays were performed to define the relationship between NEAT1 and ALKBH5. NEAT1 is a potential binding lncRNA of ALKBH5. NEAT1 was overexpressed in GC cells and tissue. Additional experiments confirmed that knockdown of NEAT1 significantly repressed invasion and metastasis of GC cells. ALKBH5 affected the m
6
A level of NEAT1. The binding of ALKBH5 and NEAT1 influences the expression of EZH2 (a subunit of the polycomb repressive complex) and thus affects GC invasion and metastasis. Our findings indicate a novel mechanism by which ALKBH5 promotes GC invasion and metastasis by demethylating the lncRNA NEAT1. They may be potential therapeutic targets for GC.
Background
The impacts of chronic airway diseases on coronavirus disease 2019 (COVID‐19) are far from understood.
Objective
To explore the influence of asthma and chronic obstructive pulmonary ...disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID‐19 patients.
Methods
A total of 961 hospitalized COVID‐19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin‐converting enzyme II (ACE2) expression. BEAS‐2B cell line was stimulated with various cytokines.
Results
In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525‐360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461‐267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID‐19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF‐α, IL‐2 receptor, IL‐10, IL‐8, and IL‐6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐4 and IL‐13 downregulated, but TNF‐α, IL‐12, and IL‐17A upregulated ACE2 expression in BEAS‐2B cells.
Conclusion
Patients with asthma and COPD likely have different risk of severe COVID‐19, which may be associated with different ACE2 expression.
After adjusting for confounding factors, COVID‐19 patients with COPD have higher risks of developing severe illness and acute respiratory distress syndrome than COVID‐19 patients with asthma. COPD patients have increased, whereas asthmatics have decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐17A, TNF‐α, and IL‐12 promote, while IL‐4 and IL‐13 suppress ACE2 expression in airway BEAS‐2B cells. Abbreviations: ACE2, angiotensin‐converting enzyme II; ARDS, acute respiratory distress syndrome; BEAS‐2B, adenovirus‐12 SV40 hybrid virus transformed bronchial epithelial cells; COPD, chronic obstructive pulmonary disease; COVID‐19, coronavirus disease 2019.
The physical mechanism of improving the photoelectric performance of InGaN/AlGaN‐based near UV light‐emitting diode (LED) with convex quantum barrier and staggered quantum well (QW) is studied by ...numerical simulation. The simulation results indicate that the voltage–current characteristics of the LED structure with convex quantum barrier and staggered QW are effectively improved compared with the traditional multiple quantum well (MQW) structure, and its electroluminescence (EL) intensity and light output power are significantly improved. The main physical mechanisms are: on the one hand, the convex quantum barrier with a lower average Al component can reduce the polarization electric field at the interface between the quantum barrier and QW as well as the effective potential barrier of holes, improve the spatial separation of electron and hole wave functions, promote the injection efficiency of carriers, and improve the uniformity of carrier distribution in the MQWs active region; On the other hand, staggered QWs can provide stronger carrier confinement effect and further increase the overlap of electron and hole wave functions, so as to improve the carrier radiative recombination efficiency; In a word, this work provides a valuable reference for obtaining high‐performance near‐ultraviolet LED.
The simulation results indicate that the voltage–current characteristics of the InGaN/AlGaN based near UV LED structure with convex quantum barrier and staggered quantum well are effectively improved compared with the traditional multi quantum well structure, and its electroluminescence intensity and light output power are significantly improved.
Gastric cancer (GC) is a common tumor-associated lethal disease, and invasiveness and metastasis are primary challenges in its clinical treatment. Hypoxia microenvironment cannot be ignored in the ...process of metastasis. Hypoxia inducible factor-1α (HIF-1α) is the core component of the hypoxia signaling pathway. The aim of this study was to identify potential hub genes and signaling pathways associated with HIF-1α. We explored the invasiveness- and metastasis-associated phenotype of GC via bioinformatics analysis and molecular studies. Differentially expressed genes (DEGs) were identified in GC cells and HIF-1α-knockdown GC cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and a protein-protein interaction (PPI) network was constructed. Hub genes were identified via centrality analysis and Molecular Complex Detection (MCODE) module analysis. The findings suggested that prolyl 4-hydroxylase beta polypeptide (P4HB) has strong associations with HIF-1α. Further, we observed that HIF-1α and P4HB were upregulated in SGC-7901 and BGC-823 cells. In addition, inhibition of HIF-1α expression reduced invasion and metastasis in GC cells; this effect was partially reversed by P4HB overexpression. Our results confirm that P4HB plays a significant role in the regulatory network of HIF-1α. Therefore, HIF-1α and P4HB may be considered potential biomarkers of GC.
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in ...hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1+CD14+ monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor‐infiltrating CCR1+CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro‐angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15‐CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor‐promoting inflammatory microenvironment was shaped by CCL15‐CCR1 axis in human HCC. Blockade of CCL15‐CCR1 axis in HCC could be an effective anticancer therapy.
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy due to distant metastasis. RELA, a major component of the NF‐κB pathway, could serve as an oncogene through activating ...proliferation or migration‐related gene expression, including NEAT1, a well‐known oncogenic long noncoding RNA. In the current study, the expression and function of RELA and NEAT1 in PDAC were examined. The potential upstream regulatory microRNAs of RELA were screened and verified for their correlation with RELA and NEAT1. The expression and function of the selected miR‐302a‐3p were evaluated. RELA and NEAT1 expression were upregulated in PDAC tissues, particularly in PDAC tissues with lymph node metastasis, and their expression correlated with clinical parameters. RELA overexpression promoted PDAC cell proliferation and migration, which could be partially attenuated by the NEAT1 knockdown. By binding to RELA, miR‐302a‐3p inhibited RELA expression, as well as PDAC cell proliferation and migration. RELA downstream NEAT1 expression was negatively regulated by miR‐302a‐3p; the suppressive effect of NEAT1 knockdown on PDAC cell proliferation and migration was partially attenuated by miR‐302a‐3p inhibition. Moreover, through direct binding, the expression of miR‐302a‐3p was also negatively regulated by NEAT1. The expression of miR‐302a‐3p was downregulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR‐302a‐3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1, and miR‐302a‐3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.
The expression of miR‐302a‐3p was down‐regulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR‐302a‐3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1 and miR‐302a‐3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.
Background
The contribution of B‐cell subsets and T‐B cell interaction to the pathogenesis of allergic rhinitis (AR) and mechanisms of allergen immunotherapy (AIT) remain poorly understood. This ...study aimed to outline circulating B‐cell signature, the underlying mechanism, and its association with clinical response to AIT in patients with AR.
Methods
IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies and phenotypes of B cells. Correlations between B cells, T cells, antigen‐specific IgE, and disease severity in AR patients were investigated. Switched memory B cells were co‐cultured with type 2 follicular helper T (Tfh2) cells and follicular regulatory T (Tfr) cells. Associations between B‐cell subsets and clinical benefits of AIT were analyzed.
Results
Frequencies and absolute numbers of circulating memory B cells were increased in AR patients. CD23 expression on CD19+CD20+CD27+IgD− switched memory B cells was significantly enhanced and positively correlated with antigen‐specific IgE levels, symptom scores, and Tfh2/Tfr cell ratio in AR patients. Compared with those from healthy controls, Tfh2 cells from AR patients had a greater capacity to induce CD23 expression on switched memory B cells via IL‐4, which was unable to be sufficiently suppressed by AR‐associated Tfr cells with defective IL‐10 expression. CD23 expression on switched memory B cells was downregulated after 12‐month AIT, which positively associated with disease remission in AR patients.
Conclusion
T‐B cell interaction, bridged by CD23 expression particularly on switched memory B cells, may be involved in the disease pathogenesis and mechanism of AIT in patients with AR.
Circulating memory B cells are increased in AR patients. The enhanced expression of CD23 on switched memory B cells correlates with antigen‐specific IgE levels, symptom scores, and allergen immunotherapy efficacy in AR patients. Tfh2 cells from AR patients have a greater capacity to induce CD23 expression on switched memory B cells via IL‐4, which is unable to be sufficiently suppressed by AR‐associated Tfr cells with defective IL‐10 expression.
Abbreviations: AIT, allergen immunotherapy; AR, allergic rhinitis; HC, healthy controls; NSM, nonswitched memory; SM, switched memory; Tfh2, type 2 follicular helper T cells; Tfr, follicular regulatory T cell.
The evidential reasoning (ER) rule, with its strict probabilistic reasoning and superior uncertainty handling ability, has been widely used in the evaluation, diagnosis, and decision-making. ...Recently, a modeling approach based on the ER rule that combines the evidence constituted by a single attribute (SA_ER) has gradually attracted scholars' attention due to its good scalability and flexibility. However, in the SA_ER, the frame of discernment (FoD) is composed of a series of singleton propositions and the universal set of these propositions. Since the SA_ER has a special form of evidence structure, its reflection on the system output is incomplete. The existing FoD is unable to quantify this incompleteness, which greatly limits the development of SA_ER. In this article, an improved SA_ER approach that extends the FoD to the power set (PSA_ER) is proposed. Meanwhile, combined with the physical meaning of the model parameters, the expressions of evidence weight and reliability are deduced, respectively. Then, an intelligent optimization algorithm is used to optimize partial parameters to enhance the performance of PSA_ER. Further, the basic properties of PSA_ER are analyzed in detail from the parameter level to promote its engineering application. Finally, an engineering example is intended to demonstrate the effectiveness of the proposed approach.
Although upregulated expression of local IgD has been reported in patients with chronic rhinosinusitis (CRS), its function is unclear.
We sought to explore the expression and function of soluble IgD ...in patients with CRS, particularly CRS with nasal polyps.
IgD levels in sinonasal mucosa were analyzed by using RT-PCR and ELISA. Numbers and phenotypes of IgD+ cells were studied by means of immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1 cells, a human mast cell line, and mast cells purified from eosinophilic polyps were cultured alone or with naive B cells purified from peripheral blood. The antigen specificity of nasal IgD was investigated by using ELISA.
The mRNA expression of immunoglobulin heavy constant delta gene, numbers of IgD+ cells, and protein levels of secretory IgD in sinonasal mucosa were increased in patients with CRS with or without nasal polyps compared with control subjects. Numbers of IgD+ plasmablasts were increased in both eosinophilic and noneosinophilic polyps, whereas numbers of IgD+ mast cells were only increased in eosinophilic polyps. Cross-linking IgD induced serum preincubated HMC-1 cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4, and IL-13 and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic polyps expression of those B cell–stimulating factors in mast cells and close contact between mast cells and B cells were found. Moreover, positive correlations of total IgD levels with total IgE levels and eosinophilia and upregulation of specific IgD against house dust mites were discovered in eosinophilic polyps.
IgD-activated mast cells can facilitate IgE production and eosinophilic inflammation in patients with CRS with nasal polyps.
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